Process for preparation of 7-alkoxy-3-bromomethylcephems

ABSTRACT

7-Alkoxy-3-bromomethyl-3-cephems are provided by reacting a 3-methylenecepham with an alkali metal salt of a lower primary alcohol in the presence of a positive brominating agent at a temperature ranging from about -80° to about 0° C. The 3-bromomethylcephems provided by this invention are useful intermediates for the preparation of known cephalosporin antibiotics.

BACKGROUND OF THE INVENTION

This invention relates to the cephalosporin class of antibiotics. Inparticular, this invention relates to a process for preparing7-alkoxy-3-bromomethyl-3-cephem compounds from 3-methylenecephams.

3-Halomethylcephems are known in the cephalosporin art and have provedto be useful intermediates for the preparation, via nucleophilicdisplacement of the halogen atom, of many related cephalosporinantibiotic compounds. 3-Halomethylcephems have heretofore been availableby allylic halogenation of the corresponding desacetoxycephalosporincompounds (U.S. Pat. Nos. 3,637,678 and 3,705,897) and by halogenationof the corresponding desacetylcephalosporins (U.S. Pat. No. 3,658,799).More recently 3-halomethylcephams have been prepared by cleavage of3-acetoxymethyl and 3-carbamoyloxymethyl cephems with hydrohalic acids[S. Karady, T. Y. Cheng, S. H. Pines and M. Sletzinger, TetrahedronLetters, 30, 2625 (1974)].

It is an object of this invention to provide a novel process for thepreparation of 7-alkoxy-3-bromomethylcephems from 3-methylenecephams.

SUMMARY OF THE INVENTION

This invention is directed to a process for preparing7-alkoxy-3-bromomethylcephems represented by the general formula##STR1## by reacting in an inert organic solvent a 3-methylenecepham ofthe formula ##STR2## with an alkali metal salt of a primary C₁ -C₇alcohol in the presence of a positive brominating agent at sub-ambienttemperatures, preferably between -80° and -20° C. wherein in the aboveformulae q is 1 or 0 representing a sulfoxide or sulfide respectively; Ris a carboxylic acid protecting group, preferably one which can bereadily removed so as to provide the carboxylic acid form of the3-bromomethylcephem or compounds derived therefrom; R₁ ' is lower alkyl;and R₂ is preferably an acylamino group, representing a wide variety ofknown penicillin and cephalosporin side chains includingphenylacetamido, phenoxyacetamido, 2-thienylacetamido,phenylglycylamido, mandelamido, and like groups.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides a process for preparing a7-alkoxy-3-bromometylcephem compound of the formula ##STR3## whichcomprises reacting a compound of the formula ##STR4## with from about 4to about 8 equivalents of an alkali metal salt of a C₁ -C₇ primaryalcohol of the formula R₁ 'OH in the presence of about 4 to about 8equivalents of a positive brominating agent selected from the groupconsisting of bromine, DBU hydrobromide perbromide, iodine monobromideand tert-butyl hypobromite in an inert organic solvent at a temperatureof -80° to about 0° C. wherein in the above formulae

q is 1 or 0;

R is a carboxylic acid protecting group;

R₁ ' is C₁ to C₆ primary alkyl or benzyl;

R₂ is an amido group of the formula ##STR5## wherein R₃ is a. hydrogen,C₁ -C₃ alkyl, halomethyl, 3-(2-chlorophenyl)-5-methylisoxazol-4-yl or4-protected amino-4-protected carboxybutyl;

b. benzyloxy, 4-nitrobenzyloxy, 2,2,2-trichloroethoxy, tert-butoxy, or4-methoxybenzyloxy;

c. the group --R" wherein R" is 1,4-cyclohexadienyl, phenyl or phenylsubstituted with 1 or 2 substituents independently selected from thegroup consisting of halo, protected hydroxy, nitro, cyano,trifluoromethyl, C₁ -C₃ alkyl, and C₁ -C₇ alkoxy;

d. an arylalkyl group of the formula

    R"--(O).sub.m --CH.sub.2 --

wherein R" is as defined above, and m is 0 or 1;

e. substituted arylalkyl group of the formula ##STR6## wherein R'" is R"as defined above, 2-thienyl or 3-thienyl, and W is protected hydroxy orprotected amino; or

f. a heteroarylmethyl group of the formula

    R""--CH.sub.2 --

wherein R"" is 2-thienyl, 3-thienyl, 2-furyl, 2-thiazolyl, 5-tetrazolyl,1-tetrazolyl, or 4-isoxazolyl;

with the limitation that when R'" or R"" is 2-thienyl. 3-thienyl, or2-furyl the reaction is carried out at a temperature below about -40° C.and a halogen quenching agent is added before the reaction mixture isallowed to warm above about 0° C.

In the foregoing definition of the process of the present invention theterm "C₁ -C₃ alkyl" refers to methyl, ethyl, n-propyl or isopropyl. Theterm "C₁ -C₇ alkoxy" refers to such groups as methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, tert-butoxy, cyclohexyloxy, benzyloxyand like groups. The term "C₁ -C₆ primary alkyl" refers to methyl,ethyl, n-propyl, n-butyl, isobutyl, n-pentyl and n-hexyl. Illustrativeof an "alkali salt of a primary C₁ -C₇ alcohol" are lithium methoxide,sodium ethoxide, potassium ethoxide, lithium butoxide, sodiumbenzyloxide, and sodium n-propoxide.

When in the above definition R" represents a substituted phenyl group,R" can be a mono or disubstituted halophenyl group such as4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl,3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl,3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl and the like;a protected hydroxy phenyl group such as 4-benzyloxyphenyl,3-benzyloxyphenyl, 4-tert-butoxyphenyl, 4-tetrahydropyranyloxyphenyl,4-(4-nitrobenzyloxy)phenyl, 2-phenacyloxyphenyl, 4-benzhydroxyphenyl,4-trityloxyphenyl and like groups; a nitrophenyl group such as3-nitrophenyl or 4-nitrophenyl; a cyanophenyl group, for example,4-cyanophenyl; a mono or dialkyl substituted phenyl group such as4-methylphenyl, 2,4-dimethylphenyl, 2-ethylphenyl, 4-isopropylphenyl,4-ethylphenyl, 3-n-propylphenyl and the like; a mono or dialkoxyphenylgroup, for example, 2,6-dimethoxyphenyl, 4-methoxyphenyl,3-ethoxyphenyl, 4-isopropoxyphenyl, 4-tert-butoxyphenyl,3-ethoxy-4-methoxyphenyl and the like. Also, R" represents disubstitutedphenyl groups wherein the substituents can be different for example,3-methyl-4-methoxyphenyl, 3-chloro-4 -benzyloxyphenyl,2-methoxy-4-bromophenyl, 4-ethyl-2-methoxyphenyl,3-chloro-4-nitrophenyl, 2-methyl-4-chlorophenyl and like disubstitutedphenyl groups bearing different substituents.

The term "protected amino" as employed in the above definition hasreference to an amino group substituted with one of the commonlyemployed amino blocking groups such as the tert-butoxycarbonyl group(t-BOC); the benzyloxycarbonyl group, the 4-methoxybenzyloxycarbonylgroup, the 4-nitrobenzyloxycarbonyl group, or the2,2,2-trichloroethoxycarbonyl group. Like conventional amino protectinggroups such as those described by J. W. Barton in "Protective Groups inOrganic Chemistry," J. F. W. McOmie, Ed., Plenum Press, New York, N.Y.,1973, Chapter 2 shall be recognized as suitable.

The term "protected hydroxy" has reference to the readily cleavablegroups formed with an hydroxyl group such as the formyloxy group, thechloroacetoxy group, the benzyloxy group, the benzhydryloxy group, thetrityloxy group, the 4-nitrobenzyloxy group, the trimethylsilyloxygroup, the phenacyloxy group, the tert-butoxy group, the methoxymethoxygroup, the tetrahydropyranyloxy group, and the like. Other hydroxyprotecting groups, including those described by C. B. Reese in"Protective Groups in Organic Chemistry", supra, Chapter 3 shall beconsidered as within the term "protected hydroxy" as used herein.

The term "protected carboxy" has reference to a carboxy group which hasbeen protected by one of the commonly used carboxylic acid protectinggroups employed to block or protect the carboxylic acid functionalitywhile reactions involving other functional sites of the compound arecarried out. Such protected carboxy groups are noted for their ease ofcleavage by hydrolytic or by hydrogenolytic methods to the correspondingcarboxylic acid. Examples of carboxylic acid ester protecting groupsinclude methyl, tert-butyl, benzyl, 4-methoxybenzyl, C₂ -C₆alkanoyloxymethyl, 2-iodoethyl, 4-nitrobenzyl, diphenylmethyl(benzhydryl), phenacyl, p-halophenacyl, 2,2,2-trichloroethyl,succinimidomethyl, tri(C₁ -C₃ alkyl)silyl and like ester formingmoieties. Other known conventional carboxy protecting groups such asthose described by E. Haslam in "Protective Groups in OrganicChemistry", supra, Chapter 5, shall be recognized as suitable. Thenature of such ester forming groups is not critical so long as theparticular ester formed therewith is stable under the reactionconditions described hereinafter. Preferred carboxylic acid esterprotecting groups are tert-butyl, 4-methoxybenzyl, benzhydryl,4-nitrobenzyl, and 2,2,2-trichloroethyl.

In the foregoing definitions, hydroxy, amino, and carboxy protectinggroups are not exhaustively defined. The function of such groups is toprotect the reactive functional groups during the preparation of thedesired products and then be removed without disrupting the remainder ofthe molecule. Many such protective groups are well known in the art andthe use of other groups equally applicable to the process and compoundsof the present invention shall be recognized as suitable. Thus, there isno novelty or inventiveness asserted with regard to the protectinggroups alluded to in this specification nor is it intended that theinvention be limited by the groups specifically disclosed herein.

Likewise the nature of the side chain group R₂ is not critical to theprocess of the present invention, that is, the process of converting a3-methylenecepham to a 3-bromomethylcephem. It should be noted, however,that some side chain groups, notably those containing a thienyl or furylmoiety, are particularly susceptible to halogenation on the heteroarylgroup under reaction conditions within the scope of the presentinvention. As detailed hereinbelow, however, special precautions,including the use of halogen quenching agents preferably in conjunctionwith lower reaction temperatures, can be employed to minimize thepossibility of concommitant side chain halogenation during theconversion to which the present process is directed. Since the sidechains on the product of the process of this invention and on compoundsderived therefrom are often subsequently cleaved, and the resultingnucleus esters then reacylated, possible side chain halogenation doesnot affect the utility of the process of this invention.

Representative of the acylamino group, ##STR7## as defined hereinaboveare formamido, acetamido, propionamido, butyramido, 2-pentenoylamino,chloroacetamido, bromoacetamido,5-tert-butoxycarbonylamino-5-tert-butoxycarbonylvaleramido, and thelike.

Illustrative of the particular acylamino group, ##STR8## are benzamido,2,6-dimethoxybenzamido, 4-chlorobenzamido, 4-methylbenzamido,3,4-dichlorobenzamido, 4-cyanobenzamido, 3-bromobenzamido,3-nitrobenzamido and the like.

Exemplary of the acylamino group ##STR9## when R₃ is a group of theformula R"(O)_(m) CH₂ -- and m is O, are cyclohexa-1,4-dienylacetamido,phenylacetamido, 4-chlorophenylacetamido, 3-methoxyphenylacetamido,3-cyanophenylacetamido, 3-methylphenylacetamido, 4-bromophenylacetamido,4-ethoxyphenylacetamido, 4-nitrophenylacetamido,3,4-dimethoxyphenylacetamido and the like; and when m is 1,representative acylamino groups are phenoxyacetamido,4-cyanophenoxyacetamido, 4-chlorophenoxyacetamido,3,4-dichlorophenoxyacetamido, 2-chlorophenoxyacetamido,4-methoxyphenoxyacetamido, 2-ethoxyphenoxyacetamido,3,4-dimethylphenoxyacetamido, 4-isopropylphenoxyacetamido,3-cyanophenoxyacetamido, 3-nitrophenoxyacetamido and like substitutedphenoxyacetamido groups.

Illustrative of the acylamino groups when R₃ is a substituted arylalkylgroup of the formula ##STR10## and when W is protected hydroxy are2-formyloxy-2-phenylacetamido, 2-benzyloxy-2-(4-methoxyphenyl)acetamido,2-(4-nitrobenzyloxy)-2-(3-chlorophenyl)acetamido,2-chloroacetoxy-2-(4-methoxyphenyl)acetamido,2-benzyloxy-2-phenylacetamido,2-trimethylsilyloxy-2-(4-chlorophenyl)acetamido,2-benzhydryloxy-2-phenylacetamido and like groups. Representative ofsuch groups when W is protected amino are2-(4-nitrobenzyloxycarbonylamino)-2-(2-thienyl)acetamido,2-(2,2,2-trichloroethoxycarbonylamino)-2-phenylacetamido,2-chloroacetamido-2-(1,4-cyclohexadien-1-yl)acetamido,2-(4-methoxybenzyloxycarbonylamino)-2-(4-methoxyphenyl)acetamido,2-benzhydryloxycarbonylamino-2-(3-thienyl)acetamido,2-(4-nitrobenzyloxycarbonyl)amino-2-phenylacetamido, and like groups.

Exemplary of the acylamino group ##STR11## when R₃ is a heteroarylmethylgroup of the formula R""--CH₂ -- are 2-thienylacetamido,3-thienylacetamido, 2-furylacetamido, a 2-thiazolylacetamido group ofthe formula ##STR12## a 1-tetrazolylacetamido group of the formula##STR13## a 5-tetrazolylacetamido group of the formula ##STR14## or a3-(2-chlorophenyl)-5-methylisoxazol-4-ylamido group of the formula##STR15##

Preferred acylamino groups include formamido, acetamido,4-nitrobenzyloxycarbonylamino, phenoxyacetamido, phenylacetamido and2-thienylacetamido. Phenylacetamido and phenoxyacetamido are mostpreferred.

In general, the process of the present invention is directed to thepreparation of 7-alkoxy-3-bromomethylcephem compounds by the reaction of3-exomethylenecephams with an alkoxide base in the presence of apositive brominating agent.

The nature of the 7-alkoxy substituent on the procuct cephems isdetermined by the particular primary alkoxide base employed in theprocess. Thus, for example when lithium ethoxide is employed, a7-ethoxy-3-halomethylcephem is produced.

The starting materials for the process of the present invention,3-exomethylenecephams, were first disclosed as a generic class in U.S.Pat. No. 3,275,626. 7-Amino and 7-acylamino 3-exomethylenecephams can beprepared by the electroreduction (pH 2 -7) of the correspondingcephalosporin compounds having a 3-substituted methyl group such asacyloxymethyl, acylthiomethyl or quarternary ammonium methyl (U.S. Pat.No. 3,792,995). Alternatively the exomethylenecepham starting materialsfor the present invention can be prepared in accordance with theprocedure of R. R. Chauvette and P. A. Pennington in the Journal ofOrganic Chemistry, 38, 2994 (1973) in which 3-methylenecephams areprepared from cephalosporanic acids by first treating thecephalosporanic acids with selected sulfur nucleophiles such asthiourea, thiobenzoic acid, potassium ethyl xanthate or sodiumthiosulfate and then reducing the respective product, C₃-(substituted)thiomethyl cephem derivatives, with either Raney nickel inaqueous ethanol or zinc in formic acid-dimethylformamide.Cephalosporanic acid derivatives have also been converted to3-exomethylenecephams on treatment with chromium (II) salts in aqueousmedia [M. Ochiai et al., J. Chem. Soc. Chemical Communications, 800(1972)]. The 3-exomethylene cepham sulfoxide starting materials for theprocess of the present invention are prepared by oxidation of thecorresponding sulfides with an equivalent amount ofmethachloroperbenzoic acid.

Although the manner in which the reactants for the process of thisinvention are combined is not critical, it is most preferred that thebase is not contacted with the exomethylenecepham starting materialwithout the halogenating agent being present. It should be noted,however, that the bases employed in the process of this invention willreact with the exomethylenecepham in the absence of halogenating agents,at varying rates depending on the reaction temperature, to providedesacetoxymethylcephalosporins. Such conversions have been reported inthe chemical literature [R. R. Chauvette and P. A. Pennington, Journalof Organic Chemistry, 38, 2994 (1973)]. If the base and theexomethylenecepham are combined, it is therefore preferred that thebrominating agent be present in the mixture or that it be addedimmediately thereafter. The conversion of 3-exomethylenecephams to3-halomethylcephems is typically carried out by adding a solution of thesubstrate 3-exomethylenecepham to a stirred solution of an alkali metalsalt of a C₁ -C₇ primary alcohol and the positive brominating agent inan inert organic solvent.

Any of a wide variety of inert organic solvents may be employed as themedium for the halogenation process of this invention. By "inert organicsolvent" is meant an organic solvent which, under the conditions of theprocess, does not enter into any appreciable reaction with either thereactants or the products. A dry aprotic organic solvent is preferred.Trace amounts of water such as that found in commercially driedsolvents, can be tolerated; however, it is generally preferred that theprocess of this invention, be carried out under anhydrous conditions.Suitable solvents include, for example, aromatic hydrocarbons such asbenzene, chlorobenzene, toluene, ethylbenzene, xylene and the like;halogenated aliphatic hydrocarbons such as chloroform, methylenechloride, carbon tetrachloride, 1,2-dichloroethane (ethylene chloride),1,1,2;-trichloroethane, 1,1-dibromo-2-chloroethane, and the like;aliphatic nitriles such as acetonitrile or propionitrile; esters such asethyl acetate, butyl acetate, and the like; ethers such as 1,4-dioxane,tetrahydrofuran, diethyl ether, dimethoxyethane and the like; amidessuch as N,N-dimethylformamide, N,N-dimethylacetamide orhexamethylphosphoric triamide (HMPA); and any other appropriate aproticsolvents. Preferred solvents or solvent mixtures are those having afreezing point below about -10° C. Highly preferred solvents for theprocess of the present invention are methylene chloride, chloroform,1,2-dichloroethane and tetrahydrofuran. Tetrahydrofuran is mostpreferred.

Suitable bases which can be employed to effectuate the conversion of theprocess of this invention are alkali metal salts of primary C₁ -C₇alcohols. The term "alkali metal salts of primary C₁ -C₇ alcohols"includes the sodium, potassium, and lithium salts of primary C₁ -C₇alcohols such as methanol, ethanol, n-propanol, benzyl alcohol,n-hexanol and like alcohols. Exemplary of such alkoxide bases suitablefor the process of this invention are lithium methoxide, sodiummethoxide, potassium ethoxide, sodium benzyloxide, lithium ethoxide,sodium n-propoxide, and like sodium, lithium and potassium salts. Thepreferred of the aforementioned bases to be employed in the process ofthis invention are the alkali metal salts of methanol or ethanol.Lithium salts thereof are more preferred; lithium methoxide is mostpreferred.

The C₇ -alkoxylation-C₃ '-bromination of the present invention isaccomplished by reacting an exomethylenecepham with from 4 to about 8equivalents of an alkali metal salt of a primary C₁ -C₇ alcohol in thepresence of from 4 to about 8 equivalents of a positive brominatingagent. The product from this conversion of the process of the presentinvention is a 7-alkoxy-3-bromomethylcephem. The best yields in thisparticular conversion have been found when about 8 equivalents each ofan alkoxide base and a brominating agent per equivalent of cephamsubstrate have been employed in conjunction with a halogen quenchingagent, the nature of which is discussed hereinbelow.

The use of lithium methoxide and tert-butyl hypochlorite under reactionconditions similar to those described for the process of this invention,to effectuate methoxylation of the C-7 position in cephalosporins andthe C-6 position in penicillins has been described in the recentchemical literature [G. A. Koppel and R. E. Koehler, Journal of theAmerican Chemical Society, 95, 2403 (1973)].

The process of the present invention is carried out at a temperatureranging from about -80° C. to about 0° C. Preferably the process iscarried out between about -80° C. and about -20° C.; however, where theside chain moiety of the cepham substrate is also subject tohalogenation, especially bromination, the process of this invention ispreferably carried out at a temperature of less than about -40° C. Suchhalogen-reactive C-7 side chains include 2-thienylacetamido,3-thienylacetamido, 2-furylacetamido and like groups. In addition toperforming the process of this invention at lower temperature when thestarting material has such halogen-reactive substituents, it isnecessary that a halogen quenching agent also be added to the reactionmixture before it is allowed to warm above about 0° C. The halogenquenching agent is added to destroy any excess brominating reagent atthe lower reaction temperature, thereby eliminating or substantiallydecreasing the likelihood of undesirable side reactions between anyexcess brominating agent and halogen-reactive side chains present on thestarting materials and the product 7-alkoxy-3-bromomethylcephems.

The term "halogen quenching agent" as employed hereinabove in describingthe process of this invention refers to those reagents not reactive withthe cepham starting materials nor the cephem products of the process ofthis invention, but capable of reacting with the brominating reagent,thereby rendering the brominating reagent or more accurately any excessthereof unreactive toward the 3-bromomethylcephem products of theprocess of this invention. Typically halogen quenching agents employedin the process of this invention are halogen reducing agents, however,other quenching agents with which the excess halogenating agent willreact preferentially (versus further reaction with the3-bromomethylcephem products) are suitable. Suitable halogen quenchingagents include di(C₁ -C₆ alkyl)sulfides, tri(C₁ -C₆ alkyl)phosphites,olefins, acetylenes, and like organic halogen reactive agents. Likewiseaqueous solutions of known reducing-inorganic salts such as bisulfite,metabisulfite, thiosulfate and dithionite salts can be successfullyemployed.

Exemplary of sulfide and phosphite halogen quenching agents useful inthe process of the present invention are dimethylsulfide,di-n-propylsulfide, dicyclohexylsulfide, methylethylsulfide,trimethylphosphite, triethylphosphite, and tri-n-butylphosphite.Representative of the olefins and acetylenes which can be employed asquenching agents in the process of this invention includediethylacetylene dicarboxylate; vinylethers including methylvinylether,ethyl vinylether and like alkylvinyl ethers; and vinylesters like vinylacetate. Exemplary of suitable reducing inorganic salts are sodiumbisulfite, potassium bisulfite, sodium metabisulfite, potassiumthiosulfate, sodium dithionite and like reducing salts.

The halogen quenching agents are typically added to the reaction mixtureafter the bromination-alkoxylation reaction has reached completion, asdetected, for example by comparative thin-layer chromatography, andpreferably before the reaction mixture is allowed to warm above about 0°C. When aqueous solutions of the aforedescribed reducing inorganic saltsare employed as quenching agents, their addition typically constitutesthe first step in the workup of the reaction mixture. However, where thereaction temperature is less than about -20° C., the aforedescribedorganic halogen quenching agents may be added to the reaction mixturebefore the halogenation reaction is initiated. Thus, for example,4'-methoxybenzyl7-(2-thienylacetamido)-7-methoxy-3-bromomethyl-3-cephem-4-carboxylatecan be prepared by adding a solution of 1 equivalent of 4'-methoxybenzyl7-(2-thienylacetamido)-3-methylenecepham-4-carboxylate intetrahydrofuran to a solution of 8 equivalents lithium methoxide, 8equivalents of bromine, and 8 equivalents of trimethylphosphite intetrahydrofuran at -60° C. The trimethylphosphite is unreactive to thebrominating agent at the lower reaction temperature, but as the reactionmixture is allowed to warm above the reaction temperature after themethoxylation-bromination is complete, the trimethylphosphite only thenreacts with the excess bromine in the mixture.

The major product of the aforedescribed example performed without thepresence of a halogen quenching agent is 4'-methoxybenzyl7-[2-(5-bromothienyl)acetamido]-7-methoxy-3-bromomethyl-3-cephem-4-carboxylate.It should be noted that although side chain halogenation is generallyundesirable, the 3-bromomethylcephem products produced in such reactionsare none the less useful in preparing other 3-bromomethylcephemcompounds. Thus, for example, the 4'-methoxybenzyl7-[2-(5-bromothienyl)acetamido]-7-methoxy-3-bromomethyl-3-cephem-4-carboxylatecan be cleaved under essentially non-aqueous side chain cleavageconditions (PCl₅, pyridine/methanol) to provide the correspondingnucleus ester 4'-methoxybenzyl7-amino-7-methoxy-3-bromomethyl-3-cephem-4-carboxylate which thereaftercan be reacylated as desired. Therefore, conversions of3-methylenecephams to 7-alkoxy-3-bromomethylcephems having, in addition,halogen substituted side chains, are also to be considered within thescope of the present invention.

The amount of quenching agent employed is not critical so long as asufficient quantity is added to render inactive the excess brominatingagent in the reaction mixture. Generally, a 1-10 fold excess or more ofthe halogen quenching agent is employed.

Although the use of halogen quenching agents in the process of thepresent invention has been found necessary only in the instances wherethe substrate exomethylenecepham has a halogen-reactive side chain,higher yields of product 3-bromomethylcephems are generally obtainedwhen such quenching agents are employed. Typically, therefore, halogenquenching agents are employed in the process of the present invention,even where the substrate exomethylenecepham does not have ahalogen-reactive side chain. The general use of halogen quenching agentsin the process of this invention is therefore preferred.

It is also preferred in the process of the present invention to add anexcess of a protic acid to the reaction mixture before it is allowed towarm above about 0° C. This optional but preferred procedure serves topreclude any undesirable side reactions between the7-alkoxy-3-bromomethylcephem product and the excess base in the reactionmixture. Both organic and inorganic protic acids are suitable.Representative of such are formic acid, acetic acid, propionic acid,trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid,hydrochloric acid, and like organic and inorganic protic acids.

The time of reaction will range generally from about 5 minutes to about1 hour with the reaction time being dependent to some extent upon theparticular reactants, the solvents employed, and the temperature atwhich the reaction is carried out. Usually the reaction will be completeafter the reactants have been maintained in contact at the preferredtemperatures for about 5 to 15 minutes. The reaction mixture can easilybe monitored, for example, by comparative thin-layer chromatography, todetermine when the bromination-alkoxylation reaction has reachedcompletion.

Exemplary of the conversions effectuated by employing the process of thepresent invention are the following:

tert-butyl 7-phenylacetamido-3-methylenecepham-4-carboxylate totert-butyl7-phenylacetamido-7-ethoxy-3-bromomethyl-3-cephem-4-carboxylate usinglithium ethoxide and tert-butyl hypobromite;

benzyl 7-(4-nitrobenzyloxycarbonylamino)-3-methylenecepham-4-carboxylateto benzyl7-(4-nitrobenzyloxycarbonylamino)-7-methoxy-3-bromomethyl-3-cephem-4-carboxylateusing lithium methoxide and tert-butyl hypobromite;

4'-nitrobenzyl 7-acetamido-3-methylenecepham-4-carboxylate 1-oxide to4'-nitrobenzyl7-acetamido-7-n-propoxy-3-bromomethyl-3-cephem-4-carboxylate-1-oxideusing bromine and sodium n-propoxide;

2',2',2'-trichloroethyl7-(2-phenyl-2-benzyloxyacetamido)-3-methylenecepham-4-carboxylate to2',2',2'-trichloroethyl-7-(2-phenyl-2-benzyloxyacetamido)-7-methoxy-3-bromomethyl-3-cephem-4-carboxylateusing bromine and sodium methoxide;

benzhydryl 7-formamido-3-methylenecepham-4-carboxylate to benzhydryl7-formamido-7-methoxy-3-bromomethyl-3-cephem-4-carboxylate using DBUhydrobromide perbromide and lithium methoxide;

2'-iodoethyl7-(2-formyloxy-2-phenylacetamido)-3-methylenecepham-4-carboxylate to2'-iodoethyl7-(2-formyloxy-2-phenylacetamido)-7-benzyloxy-3-bromomethyl-3-cephem-4-carboxylateusing tert-butyl hypobromite and lithium benzyloxide;

4'-methoxybenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate to4'-methoxybenzyl-7-phenoxyacetamido-7-methoxy-3-bromomethyl-3-cephem-4-carboxylateusing lithium methoxide and bromine;

2',2',2'-trichloroethyl7-[2-(4-nitrobenzyloxycarbonylamino)-2-phenylacetamido]-3-methylenecepham-4-carboxylateto 2',2',2'-trichloroethyl7-[2-(4-nitrobenzyloxycarbonylamino)-2-phenylacetamido]-7-propoxy-3-bromomethyl-3-cephem-4-carboxylateusing lithium propoxide and tert-butyl hypobromite;

4'-nitrobenzyl 7-(2-furylacetamido)-3-methylenecepham-4-carboxylate to4'-nitrobenzyl7-(2-furylacetamido)-7-methoxy-3-bromomethyl-3-cephem-4-carboxylateusing bromine, lithium methoxide and trimethylphosphite;

tert-butyl 7-(4-chlorophenylacetamido)-3-methylenecepham-4-carboxylateto tert-butyl7-(4-chlorophenylacetamido)-7-ethoxy-3-bromomethyl-3-cepham-4-carboxylateusing lithium ethoxide and bromine; and

4'-methoxybenzyl 7-chloroacetamido-3-methylenecepham-4-carboxylate to4'-methoxybenzyl7-chloroacetamido-7-ethoxy-3-chloromethyl-3-cephem-4-carboxylate usinglithium ethoxide and iodine monobromide.

The products produced in accordance with the process of this inventioncan be isolated and purified by employing conventional experimentaltechniques. These include chromatographic separation, filtration,crystallization and recrystallization.

The product 3-bromomethylcephem compounds of the process of thisinvention are useful as intermediates in the preparation of antibiotics.The sulfoxides can be reduced by known procedures, typically withphosphorus tribromide or phosphorus trichloride in dimethylformamide toprovide the corresponding 3-bromomethylcephems. The 3-bromomethylcephemesters are converted to active antibiotics by cleavage of the esterfunction (U.S. Pat. No. 3,658,799). Deesterification can be achieved,depending on the nature of the ester group, by any one of severalrecognized procedures, including (1) treatment with an acid such astrifluoroacetic acid, formic acid, hydrochloric acid or the like; (2)treatment with zinc and an acid such as formic acid, acetic acid orhydrochloric acid; or (3) hydrogenation in the presence of palladium,platinum, rhodium, or a compound thereof, in suspension, or on a carriersuch as barium sulfate, carbon, or alumina.

Alternatively the 7-alkoxy-3-bromomethylcephems can be converted toother 3-(substituted)methylcephem compounds by nucleophilic displacementof the bromo moiety. Such is a procedure recognized by those skilled inthe art for preparing a wide variety of known active3-heteroarylthiomethyl cephem compounds. The7-alkoxy-3-bromomethylcephem compounds provided by the process of thepresent invention are also key intermediates for the preparation ofknown clinically significant cephem antibiotics. Thus, for example,benzhydryl7-(2-thienylacetamido)-7-methoxy-3-bromomethyl-3-cephem-4-carboxylatecan be reacted with calcium carbamate, and the ester group can beremoved to provide the known antibiotic cefoxitin.

The following examples are provided to further illustrate the presentinvention. It is not intended that this invention be limited in scope byreason of any of these examples. In the following examples nuclearmagnetic resonance spectra were obtained on a Varian Associates T-60Spectrometer using tetramethylsilane as the reference standard. Thechemical shifts are expressed in δ values in parts per million (ppm) andcoupling constants (J) are expressed in cycles per second.

EXAMPLE 1 4'-Nitrobenzyl7-phenoxyacetamido-7-methoxy-3-bromoethyl-3-cephem-4-carboxylate

To a solution of 0.256 g. of dry methanol in 15 ml. of THF at -80° C.was added 4.17 of 1.85 n. methyl lithium in THF. The mixture was stirredfor 5 minutes after which time was added 0.44 ml. of bromine. To theresulting mixture was added a solution of 0.483 g. of 4'-nitrobenzyl7-phenoxyacetamido-3-methylenecepham-4-carboxylate in 4 ml. oftetrahydrofuran. After the reaction mixture was allowed to warm to 0° C.and stirred for 15 minutes at that temperature, 3 ml. oftrimethylphosphite were added. The reaction mixture was then evaporatedin vacuo and residue thereby obtained was dissolved in methylenechloride. The resulting solution of the residue was washed successivelythree times with a saturated solution of sodium chloride, once with adilute solution of sodium thiosulfate, twice with a solution of sodiumbicarbonate, and thereafter once with a saturated solution of sodiumchloride. The washed solution was then dried and evaporated in vacuo togive an impure product which was purified by preparative thin-layerchromatography using a benzene/ethyl acetate gradient to provide 140 mg.of the title product:

nmr (CDCl₃) δ 3.53 (s, 5, C₂ --H and C₆ --OCH₃), 4.42 (bs, 2, C₃--CHBr), 4.62 (s, 2, side chain CH₂), 5.14 (s, 1, C₆ --H), 5.42 (s, 2,ester CH₂), 6.8-8.4 (ArH).

The structure of the product was confirmed by comparison with anauthentic sample of p-nitrobenzyl7-phenoxy-acetamido-7-methoxy-3-bromomethyl-3-cephem-4-carboxylateprepared by 7-methoxylation of p-nitrobenzyl7-phenoxyacetamido-3-bromomethyl-3-cephem-4-carboxylate via its reactionwith lithium methoxide and t-butyl hypochlorite in tetrahydrofuran at-80° C.

EXAMPLE 2 Benzhydryl7-(2-thienylacetamido)-7-methoxy-3-bromomethyl-3-cephem-4-carboxylate.

In accordance with the procedures described by Example 1, benzhydryl7-(2-thienylacetamido)-3-methylenecepham-4-carboxylate was reacted with8 equivalents of lithium methoxide in tetrahydrofuran in the presence of8 equivalents of bromine at -80° C. to provide the title product:

nmr (CDCl₃) δ 3.41 (bs, 2, C₂ --H), 3.46 (s, 3, C₇ --OCH₃), 3.83 (s, 2,side chain CH₂), 4.20, 4.34 (ABq, 2, C₃ --CH₂ Br), 5.06 (s, 1, C₆ --H),and 6.8-7.6 (m, 14, ArH and benzhydryl CH).

I claim:
 1. A process for preparing a 3-bromomethylcephem compound ofthe formula ##STR16## which comprises reacting a compound of the formula##STR17## with from about 4 to about 8 equivalents of an alkali metalsalt of a C₁ -C₇ primary alcohol of the formula R₁ 'OH in the presenceof about 4 to about 8 equivalents of a positive brominating agentselected from the group consisting of bromine, DBU hydrobromideperbromide, iodine monobromide and tert-butyl hypobromite in an inertorganic solvent at a temperature of -80° to about -20° C. wherein in theabove formulaeq is 1 or 0; R is a carboxylic acid protecting group; R₁ 'is primary C₁ -C₆ alkyl or benzyl; and R₂ is an amido group of theformula ##STR18## wherein R₃ is a. hydrogen, C₁ -C₃ alkyl, halomethyl,3-(2-chlorophenyl)-5-methylisoxazol-4-yl or 4-protectedamino-4-protected carboxybutyl;b. benzyloxy, 4-nitrobenzyloxy,2,2,2-trichloroethoxy, tert-butoxy, or 4-methoxybenzyloxy; c. the group--R" wherein R" is 1,4-cyclohexadienyl, phenyl or phenyl substitutedwith 1 or 2 substituents independently selected from the groupconsisting of halo, protected hydroxy, nitro, cyano, trifluoromethyl, C₁-C₃ alkyl, and C₁ -C₇ alkoxy; d. an arylalkyl group of the formula

    R" --(O).sub.m --CH.sub.2 --

wherein R" is as defined above, and m is 0 or 1; e. a substitutedarylalkyl group of the formula ##STR19## wherein R'" is R" as definedabove, 2-thienyl or 3-thienyl, and W is protected hydroxy or protectedamino; or f. a heteroarylmethyl group of the formula

    R""--CH.sub.2 --

wherein R"" is 2-thienyl, 3-thienyl, 2-furyl, 2-thiazolyl, 5-tetrazolyl,1-tetrazolyl, or 4-isoxazolyl;with the limitation that when R'" or R""is2thienyl, 3-thienyl or 2-furyl the reaction is carried out at atemperature below about -40° C. and a halogen quenching agent is addedbefore the mixture is allowed to warm above about 0° C.
 2. The processof claim 1 wherein R is methyl, tert-butyl, benzyl, 4-methoxybenzyl, C₂-C₆ alkanoyloxymethyl, 2-iodoethyl, 4-nitrobenzyl, benzhydryl, phenacyl,p-halophenacyl, 2,2,2-trichloroethyl, tri(C₁ -C₃ alkyl)silyl andsuccinimidomethyl.
 3. The process of claim 2 wherein q is
 0. 4. Theprocess of claim 3 wherein the base is a lithium salt of a primary C₁-C₇ alcohol of the formula R₁ 'OH.
 5. The process of claim 4 wherein,additionally, before the reaction mixture is allowed to warm above about0°, an excess of protic acid is added to the reaction mixture.
 6. Theprocess of claim 3 wherein the brominating agent is bromine.
 7. Theprocess of claim 3 wherein the halogen quenching agent is a di(C₁ -C₆alkyl)sulfide, a tri(C₁ -C₆ alkyl)phosphite, diethylacetylenedicarboxylate, methylvinylether, ethylvinylether, vinylacetate or abisulfite, metabisulfite, thiosulfate or dithionate salt.
 8. The processof claim 3 wherein R'" or R"" is other than 2-thienyl, 3-thienyl, or2-furyl and wherein, additionally, a halogen quenching agent is added tothe reaction mixture before the reaction mixture is allowed to warmabove about 0° C.
 9. The process of claim 8 wherein the halogenquenching agent is a halogen reducing agent.
 10. The process of claim 8wherein the halogen quenching agent is a water soluble bisulfite,metabisulfite, thiosulfate or dithionite inorganic salt.
 11. The processof claim 8 wherein the halogen quenching agent is dimethylsulfide,di-n-propyl sulfide, dicyclohexyl sulfide, methyl ethyl sulfide,trimethylphosphite, triethylphosphite or tri-n-butylphosphite.
 12. Theprocess of claim 11 wherein R₃ is an arylalkyl group of the formulaR"--(O)_(m) --CH₂ -- and wherein the exomethylenecepham carboxylatestarting material is added to a solution of about 8 equivalents ofbromine, about 8 equivalents of lithium methoxide and about 10equivalents of trimethylphosphite per equivalent of exomethylenecephamin tetrahydrofuran at about -70° C. and wherein an excess of a proticacid is added to the reaction mixture before it is allowed to warm aboveabout 0° C.